Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer

Phase I/II Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer

This Phase I/II trial evaluates LOAd703 in patients with cancer (pancreatic, biliary, colorectal or ovarian) together with their standard of care chemotherapy or using gemcitabine immune-conditioning. LOAd703 is administered by intratumoral image-guided injections. Maximum 50 patients can be enrolled.

LOAd703 is an immunostimulatory gene therapy using an selection replication competent adenovirus as a gene vehicle. The virus is derived from serotype 5 adenovirus with the fiber from serotype 35. It expresses the transgenes trimerized membrane-bound isoleucine zipper (TMZ) TMZ-CD40L and 41BBL under control of a cytomegalovirus (CMV) promoter.

Study Overview

• Status: Active, not recruiting
• Conditions: Colorectal Cancer; Pancreatic Adenocarcinoma; Ovarian Cancer; Biliary Carcinoma
• Intervention / Treatment: Drug: LOAd703

Detailed Description

The trial is a Phase I/II trial evaluating the effect of LOAd703 in patients with pancreatic cancer, biliary cancer, ovarian cancer and colorectal cancer. LOAd703 is an oncolytic adenovirus serotype 5/35 encoding immunostimulatory transgenes: TMZ-CD40L and 41BBL. In Phase I, three doses (total viral load - 1x10e11, 5x10e11, 1x10e12 viral particles (VP)) of LOAd703 will be tested as add-on to standard of care or immune-conditioning gemcitabine chemotherapy. 8 treatments of LOAd703 will be delivered by image-guided intratumoral injection at the same time of chemotherapy. In Phase II stage of the study, patients will be treated at maximum tolerated dose/maximum tolerated study dose as defined in the Phase I stage. In both phases: tumor biopsies, blood samples and radiological imaging will be performed to evaluate safety, effect and mechanisms of action. Further, patients will be subjected to oral and rectal swabs, and urine sampling to determine virus shedding. The patients will be monitored for time to progression, progression free survival and overall survival.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden, 141 86
    • Karolinska University Hospital, Huddinge
  • Uppsala, Sweden, 75185
    • Uppsala University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Have histologic or cytologic evidence of colorectal carcinoma (CRC), pancreatic carcinoma (PC), biliary cancer, or epithelial ovarian carcinoma (EOC which may encompass epithelial ovarian, fallopian tube or primary peritoneal carcinoma).
2. Have advanced disease, defined as cancer that is either metastatic or locally advanced, unresectable, and for which radiotherapy or other locoregional therapies are not considered treatment of choice but systemic chemotherapy or no therapy is planned.

3. Have one of the following treatment situations apply:

   1. Colorectal carcinoma (CRC) I. A patient with refractory or recurrent metastatic CRC who has either received all conventional therapy; or is entering a "resting" phase between reasonable conventional treatments. II. A patient who is amenable to treatment with LOAd703 plus gemcitabine as a single agent conditioning regimen.
   2. Pancreatic cancer I. A patient with either locally advanced, unresectable or metastatic disease who is eligible to receive any line of conventional treatment consisting of gemcitabine and/or nab-paclitaxel. II. A patient who is amenable to treatment with LOAd703 as an "add-on" to standard-of-care gemcitabine-based or nab-paclitaxel- based regimens or gemcitabine or nab-paclitaxel as single agents. c. Biliary cancer I. A patient with either locally advanced unresectable or metastatic biliary cancer who is either treatment-naïve or has received any number of lines of treatment. II. Patient who is amenable to treatment with LOAd703 as an "add-on" to standard-of-care treatment consisting of gemcitabine combined with other agents (e.g. gemcitabine/low-dose cisplatin, gemcitabine/oxaliplatin, etc) in the first line setting or gemcitabine in a combination regimen or as a single agent in latter lines of treatment. d. Ovarian Cancer I. A patient with either epithelial ovarian, fallopian tube or primary peritoneal carcinoma.

   II. The patient has either:

   i) Residual disease following first-line standard-of-care combination chemotherapy. ii) Platinum-sensitive disease (platinum free interval ≥ 6 months) in early relapse following first-line standard-of care combination chemotherapy. iii) Platinum-resistant disease and received at least 3 lines of standard treatment. These treatments should have included bevacizumab and/or PARP inhibitors if they are reasonable candidates for such. III. Amenable to treatment with LOAd703 as an "add-on" to standard-of-care paclitaxel-based regimens (excluding bevacizumab), paclitaxel as a single agent, or gemcitabine as a single agent.

4. Have a disease burden that is considered low (i.e. low tumor burden), which is defined on a patient-by-patient basis as per principal investigator's discretion. A rough guideline for defining low tumor burden is that the sum of the product of the bidimensional measurements for all lesions is < 70 cm2.
5. Have a measurable disease by standard imaging techniques per RECIST criteria. Measurable lesions must be outside of any prior radiation field(s), unless disease progression has been documented at that disease site subsequent to radiation.
6. At least one non-irradiated (or irradiated but disease progression documented at the site subsequent to radiation) lesion must be suitable for image-guided intratumoral injection and needle biopsy.
7. Be medically suited to sedation if required during intratumoral injections.
8. Be at least 18 years-old.
9. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.
10. Have no remaining acute toxic effects from previous anticancer therapy > grade 1 except for any grade of alopecia.

11. Have adequate baseline organ/hematological function, as demonstrated by the following:

    1. Absolute neutrophil count (ANC) ≥1.0 x 109/l
    2. Hemoglobin ≥9 g/dl
    3. Platelet count ≥ 100 x 109/l
    4. Bilirubin < 1.5 times the institutional upper limit of normal (ULN)
    5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 (3, if liver metastases are present) times the institutional ULN.
    6. Serum creatinine <2 times the institutional ULN or calculated creatinine clearance >35 mL/min
    7. Prothrombin (INR)<1.5 or prothrombin time (PT) <1.5 ULN; and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤ 1.5 times the ULN.
12. The patient must understand and be willing to provide written informed consent.

Exclusion Criteria:

1. Any concurrent treatment that would compromise the study including but not limited to continuous high dose corticosteroids (>0.5mg/kg), lymphodepleting antibodies or cytotoxic agents.
2. Treatment with high dose immune inhibitors including lymphotoxic monoclonal antibodies such as alemtuzumab (CampathR), or sirolimus (RapamuneR) and its analogs, biological therapy, cytotoxic agents or any investigational agents within 21 days of registration.
3. Ovarian carcinoma patients should not be eligible to PARP inhibitor treatment.
4. Patients on warfarin (or other anti-coagulants) are not eligible.
5. Women who are pregnant, lactating, or planning to become pregnant during the study period, or women of childbearing potential who are not using acceptable contraceptive methods. A woman is considered of childbearing potential if she is not surgically sterile or is less than 1 year since last menstrual period. Acceptable contraceptive methods are: combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion and vasectomized partner.
6. Men who do not consent to the use of condom during intercourse during study participation.
7. Known active hepatitis B or C infection, or HIV infection.
8. Patients with active, severe, autoimmune disease.
9. Uncontrolled intercurrent illness including but not limited to psychiatric illness/social situations that in the opinion of the Investigator would compromise compliance of study requirements or put the patient at unacceptable risk.
10. Other malignancies within the past 2 years (not including basal and squamous cell carcinoma of the skin, localized prostate cancer or in situ cervix carcinoma).
11. Patients must agree to not to vaccinate with living vaccines during participation in the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LOAd703; LOAd703 oncolytic adenovirus administered add-on to standard of care chemotherapy or gemcitabine immune-conditioning if standard of care is no longer an option (e.g. after last line)	Drug: LOAd703; Oncolytic adenovirus serotype 5/35 encoding TMZ-CD40L and 4-1BBL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: Toxicity symptoms graded according to CTCAE v4.x.	Toxicity symptoms graded according to CTCAE v4.x.	Up to 50 weeks
Tolerability: Immune reactions to LOAd703 virus as assessed by anti-adenovirus Ig ELISA	Immune reactions to LOAd703 virus as assessed by anti-adenovirus Ig ELISA	Up to 50 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response on tumor size	Local and distant anti-tumoral size changes assessed by appropriate imaging accordingly to RECIST 1.1	Up to 50 weeks
Overall survival	Months of survival from registration	From registration date to date of death, assessed up to 40 months
Time to progression	Time to progression from registration	From registration date to date of progression, assessed up to 40 months
Progression free survival	Months of progression free survival from registration	From registration date to date of progression, or date of death, which ever came first, assessed up to 40 months
Systemic immune activation	Cytokine relative increase in blood evaluated by cytokine array	Up to 50 weeks
Immune cell activation	Upregulation of activation marker compared to baseline (fold change) evaluated by flow cytometry	Up to 50 weeks
Presence LOAd703 virus in blood	LOAd703 virus particles (vp) detected in blood (VP/ml) investigated by quantitative PCR at several time points before and after LOAd703 virus treatment	Up to 50 weeks

Collaborators and Investigators

• Sponsor: Lokon Pharma AB
• Collaborators: Uppsala University
• Investigators: Study Chair: Angelica Loskog, PhD, Lokon Pharma AB

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2018
• Primary Completion (Actual): August 22, 2023
• Study Completion (Estimated): August 22, 2024

Study Registration Dates

• First Submitted: July 4, 2017
• First Submitted That Met QC Criteria: July 19, 2017
• First Posted (Actual): July 21, 2017

Study Record Updates

• Last Update Posted (Estimated): February 1, 2024
• Last Update Submitted That Met QC Criteria: January 31, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Other Study ID Numbers: LOKON002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes